The present invention relates to the preparation of cyclic products by selective olefin metathesis of bifunctional or polyfunctional substrates in the presence of one or more homogeneous or heterogeneous metathesis catalysts in a reaction medium, characterized in that the substrates contain two or more functional groups in the form of substituted or unsubstituted alkene or alkyne moieties, and the reaction medium essentially consists of compressed carbon dioxide. The invention further relates to the preparation of cyclic or polymeric products by the process mentioned wherein the reaction temperature and the total pressure are mutually adjusted in such a way that the density of the reaction medium is within a range of d=0.2-1.5 gxc2x7cmxe2x88x923, and the product distribution is essentially controlled by the density of the reaction medium. xe2x80x9cOlefin metathesisxe2x80x9d means the mutual transalkylideneation of alkenes. Reactions of this kind are usually catalyzed by metallic compounds (review: Ivin, K. J.; Mol, J. C., Olefin Metathesis and Metathesis Polymerization, Academic Press, New York, 1997) and find applications in a wide variety of technically important processes. These include the preparation of alkenes, for example, in the Shell higher olefin process (Sherwood, M., Chem. Ind. (London) 1982, 994), in the Phillips triolefin process, and in the production of xcex1,xcfx89-diolefins (Banks, R. L. et al., J. Mol. Catal. 1982, 15, 21). Another application is the ring-opening oligomerization or polymerization of cycloalkenes (ROMP, U.S. Pat. No. 4,567,244) which is used, for example, for the production of Vestenamer(copyright) (Drxc3xa4xler, A., Der Lichtbogen 1986, 35, 24) or Norsorex(copyright) (Ohin, R. F., Chemtech 1980, 198). Further, there may be mentioned the oligomerization or polymerization of acyclic dienes (ADMET, Lindmark-Hamberg, M. et al., Macromolecules 1987, 20, 2951), the synthesis of carbo- and heterocycles having different ring sizes by ring-closure metathesis (RCM, WO 96/04289, Grubbs, R. H. et al., Acc. Chem. Res. 1995, 28, 446), crossed metatheses of different alkenes (Brxc3xcmmer, O. et al., Chem. Eur. J. 1997, 3, 441), and ene-yne metatheses (Kinoshita, A. et al., Synlett 1994, 1020; Kim, S.-H. et al., J. Org. Chem. 1996, 61, 1073). Various carbo- or heterocycles having ring sizes of xe2x89xa75 prepared by RCM have already been used for the synthesis of natural or synthetic active substances, odoriferous substances and flavors, pheromones, pharmaceuticals, crown ethers etc. (U.S. patent application Ser. No. 08/767.561 of Dec. 16, 1996, Studiengesellschaft Kohle mbH). There may be mentioned, in particular, the efficient synthesis of macrocycles by RCM (Fxc3xcrstner, A. et al., J. Org. Chem. 1996, 61, 3942), which is the basis, inter alia, of several syntheses of the antitumor drug epothilone and its analogues (Bertinato, P. et al., J. Org. Chem. 1996, 61, 8000; Nicolaou, K. C. et al., Angew. Chem. 1996, 108, 2554; Yang, Z. et al., Angew. Chem. 1997, 109, 170; Schinzer, D. et al., Angew. Chem. 1997, 109, 543).
The preparation of cyclic compounds from open-chain substrates is a central problem of chemical synthesis. Cyclizations are often performed in an intramolecular ring-closure reaction, proceeding from bifunctional or polyfunctional precursors. The desired ring-closure reactions are always competing with a polymerization of the substrates (xe2x80x9cpolymersxe2x80x9d in this connection means products formed by the linkage of two or more substrate molecules, including, in particular, dimers and oligomers of low molecular weights). This general problem also applies to the preparation of cyclic products by olefin metatheses. If this reaction is performed with bifunctional or polyfunctional substrates in which the mentioned functional groups are alkenes or alkynes, mixtures of the cyclization product and polymers are formed. In Scheme 1, this competition situation is exemplified by the metathesis reaction of the diene 1. 
In detail, the product distribution between the polymer and the cyclization product depends on the structure of the substrates, the catalyst used and the reaction conditions. The formation of the cyclization product is favored by performing the reaction in an organic solvent at a high dilution. This applies, in particular, to the preparation of medium-sized (8-11 ring members) and large-sized (xe2x89xa712 ring members) rings. In general, hydrocarbons (hexane, toluene, xylene, cumene etc.) or chlorinated hydrocarbons (dichloromethane, 1,2-dichloroethane, halobenzenes etc.) are preferred as solvents for olefin metatheses. The large reaction volumes and expensive dosage methods required for achieving the necessary high dilutions limit the maximum yields obtainable per space and time. The separation of the products present in high dilutions from the reaction mixtures further requires time- and energy-consuming separation operations, such as chromatography, rectification or distillation. The thermal stress in distillative separations may adversely affect the quality of the products obtained and often leads to an irreversible deactivation of the catalysts employed. In the synthesis of physiologically active compounds, residual solvents which may not be toxicologically safe represent a particular problem. Also with respect to possible environmental impacts, the use of large amounts of solvents involves drawbacks in terms of process technology. Therefore, methods resulting in a complete or partial elimination of the mentioned solvents are of great technical importance.
Carbon dioxide has been proposed as an ecologically safe reaction medium for metal-catalyzed reactions [reviews: Jessop, P. G. et al., Science 1995, 269, 1065; Morgenstern, D. A. et al. in: Green Chemistry (Ed.: P. T. Anastas, T. C. Williamson) ACS Symp. Ser. 262, American Chemical Society, Washington D.C., 1996, p. 132 et seq.; Dinjus, E. et al. in: Chemistry under Extreme or Non-Classical Conditions (Ed.: R. van Eldik, C. D. Hubbard), Wiley, New York, 1996, p. 219 et seq.]. Metathesis reactions in compressed (gaseous, liquid or supercritical) carbon dioxide are described in WO 96/32421; however, this includes only ring-opening polymerization (ROMP) reactions of cyclic monofunctional alkenes as substrates. We now describe a process for the preparation of chemical products by selective olefin metathesis of bifunctional or polyfunctional substrates in the presence of a homogeneous or heterogeneous metathesis catalyst in a reaction medium, characterized in that the substrates contain two or more functional groups in the form of substituted or unsubstituted alkene or alkyne moieties, and the reaction medium essentially consists of compressed (gaseous, liquid or supercritical) carbon dioxide. In particular, the present invention relates to the preparation of cyclic compounds having ring sizes of nxe2x89xa75 by the ring-closure metathesis of bifunctional or polyfunctional substrates. Surprisingly, it has been found that cyclic or polymeric products can be selectively obtained with a high selectivity by varying the density of the reaction medium.
Using the present invention, carbo- and heterocycles of arbitrary ring size n (nxe2x89xa75) including medium-sized (n=8-11) and large-sized (nxe2x89xa712) rings can be prepared. The solvents used to date in such reactions, which are in part physiologically doubtful and environmentally harmful (e.g., aromatics or chlorinated hydrocarbons), are thus completely or substantially replaced by a nontoxic, noncombustible, inexpensive reusable reaction medium. Performing the reaction in compressed carbon dioxide has the further consequence that substituents at the substrates are tolerated which are not compatible with the olefin metathesis in conventional solvents. Further, the processing of the reaction mixtures is substantially simplified due to the special solvent properties of compressed carbon dioxide, for example, by segregating the products wholly or partially from the reaction mixture, or by separating them wholly or partially from the catalyst using the extractive properties of compressed CO2 (K. Zosel, Angew. Chem. 1978, 90, 748). After separation of the products, the remaining catalysts are in part reusable for olefin metatheses.
The reaction temperature and the total pressure can be freely chosen within broad ranges in the selective olefin metathesis of bifunctional or polyfunctional substrates in compressed carbon dioxide, but they are mutually adjusted in such a way that the density of the reaction medium is within a range of d=0.2-1.5 gxc2x7cmxe2x88x923. Preferred reaction temperatures are within a range of from 250 to 400 K, particularly preferred within a range of from 280 to 345 K. Preferred total pressures are within a range of from 30 to 300 bar, particularly preferred within a range of from 50 to 220 bar. The ring-closure reaction of the bifunctional or polyfunctional substrate is favored by applying high densities while polymerization preferentially proceeds in the range of low densities. The respectively optimum range of densities depends on the structure of the substrate and on the catalyst used.
According to the present invention, the ring-closure reaction is preferably performed at densities d=0.4-1.5 gxc2x7cmxe2x88x923, more preferably at densities d=0.6-1.5 gxc2x7cmxe2x88x923. High densities are preferred, in particular, for the preparation of medium-sized and large-sized rings (for the metathesis of diene 1 to lactone 2 as a specific example, see FIG. 1), while the chosen density is less critical for the preparation of rings with n=5-7. Particularly preferred conditions for the ring-closure reaction can be seen from the appended Examples, which are not intended, however, to limit the applicability of the present invention in any way.
In contrast to cyclization, the polymerization by the metathesis of a bifunctional or polyfunctional substrate is preferably performed at low densities d=0.2-0.65 gxc2x7cmxe2x88x923 of the reaction medium which essentially consists of compressed carbon dioxide. As for the RCM, the optimum range of densities depends on the substrate and catalyst employed. For the metathesis with polymerization of diene 1 as a specific example, see FIG. 1.
As the catalysts or catalyst precursors, any metathesis-active metallic compound can be used in the present invention, irrespective of whether they are homogeneous or heterogeneous in the reaction medium as long as they are not inactivated by compressed carbon dioxide. The catalysts can be employed in isolated form or produced in situ in the reaction medium from suitable precursors. The amount of catalyst employed is not critical, preferred amounts of catalyst being within a range of from 0.01 to 10 mole percent, based on the substrate used. Preferred catalysts or catalyst precursors are transition metal-carbenes, or transition metallic compounds which form metal-carbenes under the reaction conditions, or transition metal salts in connection with an alkylating agent. These include, inter alia, systems of general types I-IX (references: type I (M=Ru, Os): WO 96/04289, Feb. 15, 1996; Nguyen et al., J. Am. Chem. Soc. 1992, 114, 3974; Nguyen et al., J. Am. Chem. Soc. 1993, 115, 9858; Schwab, P. et al., Angew. Chem. 1995, 107, 2179; Schwab, P. et al., J. Am. Chem. Soc. 1996, 118, 100; Mohr, B. et al., Organometallics 1996, 15, 4317; type II (M=Mo, W): Schrock, R. R. et al., J. Am. Chem. Soc. 1990, 112, 3875; Fujimura, O. et al., Organometallics 1996, 15, 1865; type III: Quingnard, F. et al., J. Mol. Catal. 1986, 36, 13; type IV (M=Nb, Ta): Rocklage, S. M. et al., J. Am. Chem. Soc. 1981, 103, 1440; Wallace, K. C. et al., Macromolecules 1987, 20, 448; type V (cp=substituted or unsubstituted cyclopentadienyl) : U. S. 4,567,244, Jan. 28, 1986; type VI: Herrmann, W. A. et al., Angew. Chem. 1991, 103, 1704; type VII: Nugent, W. A. et al., J. Am. Chem. Soc. 1995, 117, 8992; type VIII: Davie, E. S., J. Catal. 1972, 24, 272; type IX: Herrmann, W. A. et al., Angew. Chem. 1996, 108, 1169.). 
R1-R6 are residues which are independently selected from hydrogen, C2-C20 alkenyl, C2-C20 alkynyl, C1-C20 alkyl, aryl, C1-C20 carboxylate, C1-C20 alkoxy, C2-C20 alkenyloxy, C2-C20 alkynyloxy, aryloxy, C2-C20 alkoxycarbonyl, C1-C20 alkylthio, C1-C20 alkylsulfonyl or C1-C20 alkylsufinyl; each of which may optionally be substituted with C1-C12 alkyl, C1-C12 perfluoroalkyl, halogen, C1-C5 alkoxy or aryl. In cyclic compounds, the residues R1-R10 can be linked to one another.
X1-X3 are arbitrarily defined anionic ligands which are independently selected, especially from Fxe2x88x92, Clxe2x88x92, Brxe2x88x92, Ixe2x88x92, CNxe2x88x92, SCNxe2x88x92, R1Oxe2x88x92, R1R2Nxe2x88x92, (R1-R5)-allylxe2x88x92, (R1-R5)-cyclopentadienylxe2x88x92, the residues R1-R5 corresponding to the above definition.
L1-L3 are neutral ligands which are independently selected, especially from CO, CO2, R1NCO, R1R2Cxe2x95x90CR3R4, R1Cxe2x89xa1CR2, R1R2Cxe2x95x90NR3, R1Cxe2x89xa1N, R1OR2, R1SR2, NR1R2R3, PR1R2R3, AsR1R2R3, residues R1-R4 corresponding to the above definition.
m, n are integers of from 0 to 6. Particularly preferred catalysts or catalyst precursors are carbene complexes of general type I with L1-L2=PR1R2R3, R1-R3 corresponding to the above definition, particularly preferred residues R1-R3 being aryl or alkyl, especially secondary alkyl or cycloalkyl residues. Also particularly preferred are carbene complexes of general type II with R1=aryl and R2-R4=C1-C20 alkyl, each of which may optionally be substituted with C1-C12 alkyl, C1-C12 perfluoroalkyl, aryl, halogen.
Reactions according to the present invention may also be performed in the presence of one or more additives which may result in, for example, an easier handling of the substrates or catalysts, or an improvement of the solvent properties of the reaction medium, or an increase of the reaction rate, or an improvement of the yield. For example, such additives may be independently selected from: water, phosphorus compounds, amines, perfluorinated compounds (see Patent Application Studiengesellschaft Kohle m.b.H. DE 197 02 025.9, Jan. 23, 1997), Lewis-acidic compounds, metal alkoxides, organic solvents (e.g., dichloromethane, trichloromethane, tetrachloro-methane, 1,2-dichloroethane, trichloroethene, benzene, toluene, xylene, cumene, hexane, cyclohexane, halobenzenes, tetrahydrofuran, tert-butyl methyl ether, diethyl ether, dimethoxy-ethane, dimethylformamide, ethyl acetoacetate, acetone, dimethyl carbonate, alcohols).
In the present invention, xe2x80x9cbifunctional or polyfunctional substratesxe2x80x9d means any chemical compound which contains two or more functional groups in the form of substituted or unsubstituted alkene or alkyne moieties allowing metathesis reaction. The substrates may be either conformationally preorganized or completely flexible. In addition to the functional groups mentioned which participate in the reaction, the substrates may contain any number of further groups or heteroatoms which are compatible with the metathesis reaction. These include, inter alia, branched or unbranched alkyl residues, aromatic or non-aromatic carbocyclic rings, carboxylic acids, esters, ethers, epoxides, silyl ethers, thioethers, thioacetals, anhydrides, imines, silyl enol ethers, ammonium salts, amides, nitrites, perfluoroalkyl groups, gem-dialkyl groups, alkynes, alkenes, halogens, alcohols, ketones, aldehydes, carbamates, carbonates, urethanes, sulfonates, sulfones, sulfonamides, nitro groups, organosilane units, metal centers, oxygen-, nitrogen-, sulfur-, phosphorus-containing heterocycles. Mixtures of substrates according to the present invention may also be reacted; in this case, the substrates may be supplied to the reaction medium in admixture or sequentially. The substrates may also be in supported form.
In particular, selective olefin metatheses in compressed carbon dioxide may also be performed with bifunctional or polyfunctional substrates which contain one or more primary, secondary or tertiary basic amine units which can lead to a deactivation of the metathesis catalysts in conventional solvents.
By the selective olefin metathesis of bifunctional or poly-functional substrates in compressed carbon dioxide, there may be obtained, in particular, macrocyclic esters, ethers, amines and ketones which may be used, for example, as odoriferous substances and their precursors. The range of applications includes, inter alia, that of RCM in organic solvents (see, inter alia, U.S. patent application Ser. No. 08/767.561 of Dec. 16, 1996, Studiengesellschaft Kohle mbH). This includes, for example, the macrocyclic esters 2 and 4 and double bond-related isomers thereof (e.g., from substrates 1 and 3), which themselves have a distinct musk-like smell and are converted to the known perfume ingredients pentadecanolide and Arova 16(copyright), respectively, by hydrogenation. 
The range of application of the selective olefin metathesis of bifunctional or polyfunctional substrates in compressed carbon dioxide further comprises a series of homologous substituted or unsubstituted cyclic ketones having ring sizes of from 12 to 30 including cibetone, muscone, Exalton(copyright) and Muscenon(copyright) (review: Ohloff, G., Riechstoffe und Geruchssinn, Springer, Berlin, 1990; Bauer K. et al., Ullmann""s Encyclopedia of Industrial Chemistry, VCH, Weinheim, 5th Ed., 1988, Vol. A11, 141). The antitumor drug epothilone and its analogues can also be prepared using this reaction principle (Bertinato, P. et al., J. Org. Chem. 1996, 61, 8000; Nicolaou, K. C. et al., Angew. Chem. 1996, 108, 2554; Yang, Z. et al., Angew. Chem. 1997, 109, 170; Schinzer, D. et al., Angew. Chem. 1997, 109, 543).
The compounds prepared by selective olefin metathesis of bifunctional or polyfunctional substrates in compressed carbon dioxide are wholly or partially separated from the catalyst when the pressure is released from the reactor, and can be collected in suitable receivers. The carbon dioxide released when the products are isolated can again be employed for charging or flushing the reactor. Further, the catalyst thus separated from the product can be reused for metathesis reactions.
In integrated processes, selective olefin metatheses of bifunctional or polyfunctional substrates in compressed carbon dioxide may also be followed by further reactions in compressed carbon dioxide, such as carbon-carbon bond formation, reduction or oxidation for the further functionalization of the products obtained. In particular, by selective olefin metathesis and subsequent hydrogenation in compressed carbon dioxide as the reaction medium, saturated macrocyclic musk scents, such as Exaltolid(copyright), Arova 16(copyright) and Exalton(copyright), can be directly obtained from suitable acyclic unsaturated precursors in an integrated process.
By selective olefin metathesis of bifunctional or polyfunctional substrates in compressed carbon dioxide, unsaturated polymers, such as polymeric hydrocarbons, polyesters, polyamides, polycarbonates, polyurethanes and the like, can be prepared. These are of economical importance, e.g., as thermoplastics, elastomers, fillers, insulation materials, adsorbers and in the preparation of optical devices and as additives in vulcanization.
The polymers obtained from the reaction mixture can be further purified and processed using customary methods. Further reactions of the polymers, such as hydrogenation or oxidation, as well as known methods of polymer processing in compressed carbon dioxide [Schmeder, H. in: Chemistry under Extreme or Non-Classical Conditions (Ed.: R. van Eldik, C. D. Hubbard), Wiley, New York, 1996, p. 280 et seq.] can be applied within the scope of integrated processes. The carbon dioxide liberated when the pressure is released can again be compressed and used as a reaction medium.
The following Examples describe prototypical metathesis reactions in compressed carbon dioxide under preferred conditions without in any way limiting the scope, range of application or any advantages of the present invention. The abbreviation Cy represents cyclohexyl (cyclo-C6H11), d represents the density, and cat. means catalyst.